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Dyslipidemias pp 453-463 | Cite as

Bile Acid Sequestrants: Risk–Benefits and Role in Treating Dyslipidemias

  • Om P. GandaEmail author
  • Abhimanyu Garg
Chapter
Part of the Contemporary Endocrinology book series (COE)

Abstract

Much progress has been made during the past two decades in the management of lipid disorders and consequent reduction in mortality from cardiovascular disease. However, many people remain inadequately treated and not at lipid goals. Bile acid sequestrants (BAS) have been an effective modality for treatment of hypercholesterolemia and elevated low-density lipoprotein-cholesterol (LDL-C) for more than 50 years. Well- designed angiographic and clinical trials have documented the successful reduction in atherosclerotic burden and cardiovascular events with the use of BAS in monotherapy and combination therapy with other lipid-lowering agents.

Despite the availability of statins as the preferred agents for LDL-C lowering, BAS have proven to be of value as second-line therapy or as adjunct therapy when LDL-C goals are not achievable with statins alone. Due to a lack of systemic absorption, BAS have no major adverse effect. The newer BAS may be associated with better tolerability and side effects.

In patients with type 2 diabetes, or those at a risk of diabetes, BAS have a unique advantage of a dual effect, namely reduction in LDL-C and a modest but significant effect on reducing hyperglycemia. The precise mechanism of the glucose-lowering effect is not fully understood.

Keywords

Bile acid sequestrants Colestipol Cholestyramine Colesevelam Bile acids LDL cholesterol Farnesoid X receptor Coronary heart disease Type 2 diabetes 

Notes

Acknowledgement:

Supported, in part, by NIH Joslin Diabetes Endocrinology Research Center, DERC Core DK 036836

References

  1. 1.
    Insull W Jr. Clinical utility of bile acid sequestrants in the treatment of dyslipidemia: a scientific review. South Med J. 2006;99(3):257–73.CrossRefPubMedGoogle Scholar
  2. 2.
    Out C, Groen AK, Brufau G. Bile acid sequestrants: more than simple resins. Curr Opin Lipidol. 2012;23(1):43–55.CrossRefPubMedGoogle Scholar
  3. 3.
    Davidson MH, Dillon MA, Gordon B et al. Colesevelam hydrochloride (cholestagel): a new, potent bile acid sequestrant associated with a low incidence of gastrointestinal side effects. Arch Intern Med. 1999; 159(16):1893–900.CrossRefPubMedGoogle Scholar
  4. 4.
    Bays H, Dujovne C. Colesevelam HCl: a non-systemic lipid-altering drug. Expert Opin Pharmacother. 2003;4(5):779–90.PubMedGoogle Scholar
  5. 5.
    Goldstein JL, Brown MS. Regulation of low-density lipoprotein receptors: implications for pathogenesis and therapy of hypercholesterolemia and atherosclerosis. Circulation 1987;76(3):504–7.CrossRefPubMedGoogle Scholar
  6. 6.
    Knapp HH, Schrott H, Ma P, et al. Efficacy and safety of combination simvastatin and colesevelam in patients with primary hypercholesterolemia. Am J Med. 2001;110(5):352–60.CrossRefPubMedGoogle Scholar
  7. 7.
    Hunninghake D, Insull W Jr, Toth P, Davidson D, Donovan JM, Burke SK. Coadministration of colesevelam hydrochloride with atorvastatin lowers LDL cholesterol additively. Atherosclerosis. 2001;158(2):407–16.CrossRefPubMedGoogle Scholar
  8. 8.
    Eckel RH. Approach to the patient who is intolerant of statin therapy. J Clin Endocrinol Metab. 2010;95:2015–22.CrossRefPubMedGoogle Scholar
  9. 9.
    Knopp RH, Tsunehara C, Retzlaff BM, et al. Lipoprotein effects of combined ezetimibe and colesevelam hydrochloride versus ezetimibe alone in hypercholesterolemic subjects: a pilot study. Metabolism. 2006;55(12):1697–703.CrossRefPubMedGoogle Scholar
  10. 10.
    Cashin-Hemphill L, Mack WJ, Pogoda JM, Sanmarco ME, Azen SP, Blankenhorn DH. Beneficial effects of colestipol-niacin on coronary atherosclerosis. A 4-year follow-up. JAMA. 1990;264(23):3013–7.CrossRefPubMedGoogle Scholar
  11. 11.
    Brown G, Albers JJ, Fisher LD, et al. Regression of coronary artery disease as a result of intensive lipid-lowering therapy in men with high levels of apolipoprotein B. N Engl J Med. 1990;323(19):1289–98.CrossRefPubMedGoogle Scholar
  12. 12.
    McKenney J, Jones M, Abby S. Safety and efficacy of colesevelam hydrochloride in combination with fenofibrate for the treatment of mixed hyperlipidemia. Curr Med Res Opin. 2005;21(9):1403–12.CrossRefPubMedGoogle Scholar
  13. 13.
    Devaraj S, Chan E, Jialal I. Direct demonstration of an antiinflammatory effect of simvastatin in subjects with the metabolic syndrome. J Clin Endocrinol Metab. 2006;91(11):4489–96.CrossRefPubMedGoogle Scholar
  14. 14.
    Bays HE, Davidson M, Jones MR, Abby SL. Effects of colesevelam hydrochloride on low-density lipoprotein cholesterol and high-sensitivity C-reactive protein when added to statins in patients with hypercholesterolemia. Am J Cardiol. 2006;97(8):1198–205.CrossRefPubMedGoogle Scholar
  15. 15.
    Rosenson RS. Colesevelam HCl reduces LDL particle number and increases LDL size in hypercholesterolemia. Atherosclerosis. 2006;185(2):327–30.CrossRefPubMedGoogle Scholar
  16. 16.
    Siperstein MD, Nichols CW Jr, Chaikoff IL. Effects of ferric chloride and bile on plasma cholesterol and atherosclerosis in the cholesterol-fed bird. Science. 1953;117:386–9.CrossRefPubMedGoogle Scholar
  17. 17.
    Tennent DM, Siegel H, Zanetti ME, et al. Plasma cholesterol lowering action of bile acid binding polymers in experimental animals. J Lipid Res. 1960;1:469–73.PubMedGoogle Scholar
  18. 18.
    Bergen SS Jr, Van Itallie TB, Tennent DM, Sebrell WH. Effect of an anion exchange resin on serum cholesterol in man. Proc Soc Exp Biol Med. 1959;102:676–9.CrossRefPubMedGoogle Scholar
  19. 19.
    Hashim SA, Bergen SS Jr, Van Itallie TB. Experimental steatorrhea induced in man by bile acid sequestrant. Proc Soc Exp Biol Med. 1961;106:173–5.CrossRefPubMedGoogle Scholar
  20. 20.
    Parkinson TM, Gundersen K, Nelson NA. Effects of colestipol (U-26,597A), a new bile acid sequestrant, on serum lipids in experimental animals and man. Atherosclerosis. 1970;11:531–7.CrossRefPubMedGoogle Scholar
  21. 21.
    Lefebvre P, Cariou B, Lien F, Kuipers F, Staels B. Role of bile acids and bile acid receptors in metabolic regulation. Physiol Rev. 2009;89(1):147–91.CrossRefPubMedGoogle Scholar
  22. 22.
    Holst JJ, McGill MA. Potential new approaches to modifying intestinal GLP-1 secretion in patients with type 2 diabetes mellitus: focus on bile acid sequestrants. Clin Drug Investig. 2012;32(1):1–14.CrossRefPubMedGoogle Scholar
  23. 23.
    Braunlin W, Zhorov E, Smisek D, et al. In vitro comparison of bile acid binding to colesevalamHCL and other bile acid sequestrants. Polymer Prepr. 2000;41:708–9.Google Scholar
  24. 24.
    Davidson MH. A systematic review of bile acid sequestrant therapy in children with familial hypercholesterolemia. J Clin Lipidol. 2011;5(2):76–81.CrossRefPubMedGoogle Scholar
  25. 25.
    Suzuki T, Oba K, Igari Y, et al. Effects of bile-acid-binding resin (colestimide) on blood glucose and visceral fat in Japanese patients with type 2 diabetes mellitus and hypercholesterolemia: an open-label, randomized, case-control, crossover study. J Diabetes Complications. 2012;26(1):34–9.CrossRefPubMedGoogle Scholar
  26. 26.
    Dorr AE, Gundersen K, Schneider JC Jr, Spencer TW, Martin WB. Colestipol hydrochloride in hypercholesterolemic patients–effect on serum cholesterol and mortality. J Chronic Dis. 1978;31(1):5–14.CrossRefPubMedGoogle Scholar
  27. 27.
    No Authors. The Lipid Research Clinics Coronary Primary Prevention Trial results. I. Reduction in incidence of coronary heart disease. JAMA. 1984;251(3):351–64.CrossRefGoogle Scholar
  28. 28.
    No Authors. The Lipid Research Clinics Coronary Primary Prevention Trial results. II. The relationship of reduction in incidence of coronary heart disease to cholesterol lowering. JAMA. 1984;251(3):365–74.CrossRefGoogle Scholar
  29. 29.
    Brensike JF, Levy RI, Kelsey SF, et al. Effects of therapy with cholestyramine on progression of coronary arteriosclerosis: results of the NHLBI Type II Coronary Intervention Study. Circulation. 1984;69(2):313–24.CrossRefPubMedGoogle Scholar
  30. 30.
    Watts GF, Lewis B, Brunt JN, et al. Effects on coronary artery disease of lipid-lowering diet, or diet plus cholestyramine, in the St Thomas' Atherosclerosis Regression Study (STARS). Lancet. 1992;339(8793):563–9.CrossRefPubMedGoogle Scholar
  31. 31.
    Kane JP, Malloy MJ, Ports TA, Phillips NR, Diehl JC, Havel RJ. Regression of coronary atherosclerosis during treatment of familial hypercholesterolemia with combined drug regimens. JAMA. 1990;264(23):3007–12.CrossRefPubMedGoogle Scholar
  32. 32.
    Whitney EJ, Krasuski RA, Personius BE, et al. A randomized trial of a strategy for increasing high-density lipoprotein cholesterol levels: effects on progression of coronary heart disease and clinical events. Ann Intern Med. 2005;142(2):95–104.CrossRefPubMedGoogle Scholar
  33. 33.
    No Authors. The Lipid Research Clinics Coronary Primary Prevention Trial. Results of 6 years of post-trial follow-up. The Lipid Research Clinics Investigators. Arch Intern Med. 1992;152(7):1399–410.CrossRefGoogle Scholar
  34. 34.
    Garg A, Grundy SM. Cholestyramine therapy for dyslipidemia in non-insulin-dependent diabetes mellitus. A short-term, double-blind, crossover trial. Ann Intern Med. 1994;121(6):416–22.CrossRefPubMedGoogle Scholar
  35. 35.
    Bays HE, Goldberg RB, Truitt KE, Jones MR. Colesevelam hydrochloride therapy in patients with type 2 diabetes mellitus treated with metformin: glucose and lipid effects. Arch Intern Med. 2008;168(18):1975–83.CrossRefPubMedGoogle Scholar
  36. 36.
    Fonseca VA, Rosenstock J, Wang AC, Truitt KE, Jones MR. Colesevelam HCl improves glycemic control and reduces LDL cholesterol in patients with inadequately controlled type 2 diabetes on sulfonylurea-based therapy. Diabetes Care. 2008;31(8):1479–84.CrossRefPubMedCentralPubMedGoogle Scholar
  37. 37.
    Goldberg RB, Fonseca VA, Truitt KE, Jones MR. Efficacy and safety of colesevelam in patients with type 2 diabetes mellitus and inadequate glycemic control receiving insulin-based therapy. Arch Intern Med. 2008;168(14):1531–40.CrossRefPubMedGoogle Scholar
  38. 38.
    Fonseca VA, Handelsman Y, Staels B. Colesevelam lowers glucose and lipid levels in type 2 diabetes: the clinical evidence. Diabetes Obes Metab. 2010;12(5):384–92.CrossRefPubMedCentralPubMedGoogle Scholar
  39. 39.
    Rosenstock J, Fonseca VA, Garvey WT, et al. Initial combination therapy with metformin and colesevelam for achievement of glycemic and lipid goals in early type 2 diabetes. Endocr Pract. 2010;16(4):629–40.CrossRefPubMedGoogle Scholar
  40. 40.
    Handelsman Y, Goldberg RB, Garvey WT, et al. Colesevelam hydrochloride to treat hypercholesterolemia and improve glycemia in prediabetes: a randomized, prospective study. Endocr Pract. 2010;16(4):617–28.CrossRefPubMedGoogle Scholar
  41. 41.
    Davidson MH. Interrupting bile-acid handling and lipid and glucose control: effects of colesevelam on glucose levels. J Clin Lipidol. 2008;2(2):S29–33.CrossRefPubMedGoogle Scholar
  42. 42.
    Goldfine AB. Modulating LDL cholesterol and glucose in patients with type 2 diabetes mellitus: targeting the bile acid pathway. Curr Opin Cardiol. 2008;23(5):502–11.CrossRefPubMedGoogle Scholar
  43. 43.
    Vallim TQ, Edwards PA. Bile acids have the gall to function as hormones. Cell Metab. 2009;10(3):162–4.CrossRefPubMedGoogle Scholar
  44. 44.
    Beysen C, Murphy EJ, Deines K, et al. Effect of bile acid sequestrants on glucose metabolism, hepatic de novo lipogenesis, and cholesterol and bile acid kinetics in type 2 diabetes: a randomised controlled study. Diabetologia. 2012;55(2):432–42.CrossRefPubMedGoogle Scholar
  45. 45.
    Henry RR, Aroda VR, Mudaliar S, Garvey WT, Chou HS, Jones MR. Effects of colesevelam on glucose absorption and hepatic/peripheral insulin sensitivity in patients with type 2 diabetes mellitus. Diabetes Obes Metab. 2012; 14(1):40–6.CrossRefPubMedGoogle Scholar
  46. 46.
    Mazze R, Strock E, Monk A, et al. Diurnal glucose patterns based on contimnuous glucose monitoring of patients with type 2 diabetes treated with colesevelam. Diabetes. 2012;61(suppl 1):A 301.Google Scholar
  47. 47.
    Stone NJ, Robinson J, Lichtenstein AH, et al. Treatment of blood cholesterol to reduce atherosclerotic cardiovascular disease risk in adults: synopsis of the 2013 American College of Cardiology/American Heart Association cholesterol guideline. Ann Intern Med. 2014;160(5):339–43.CrossRefPubMedGoogle Scholar
  48. 48.
    Jacobsen TA, Ito MK, Maki KC et al National Lipid Association recommendations for patient-centered management of dyslipidemia: Part 1 – executive summary. J Clin Lipidology 2014;8:473–488.Google Scholar
  49. 49.
    Scheel PJ Jr, Whelton A, Rossiter K, Watson A. Cholestyramine-induced hyperchloremic metabolic acidosis. J Clin Pharmacol. 1992;32(6):536–8.CrossRefPubMedGoogle Scholar
  50. 50.
    Brook, RD, Bard, RL, Rubenfire M. Images in cardiovascular medicine: xanthomas triggered by bile acid sequestrants. J Clin Lipidol. 2008;2:58–9.CrossRefPubMedGoogle Scholar

Copyright information

© Humana Press 2015

Authors and Affiliations

  1. 1.Lipid Clinic, Clinical Research sectionJoslin Diabetes CenterBostonUSA
  2. 2.Harvard Medical SchoolBostonUSA
  3. 3.Beth Israel Deaconess medical CtrDepartment of MedicineBostonUSA
  4. 4.Department of Internal MedicineUT Southwestern Medical CenterDallasUSA

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